Leflunomide is a disease-modifying antirheumatic drug (DMARD), used in active moderate to severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor. Leflunomide is an immunomodulatory drug inhibiting mitochondrial enzyme dihydroorotate dehydrogenase, which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA). Leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their ribonucleotides by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.
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